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C L Faingold

Publications and source records attributed to C L Faingold.

At least 55 records · Page 3Linked to original sources
PubMed1991

Involvement of GABA in acoustically-evoked inhibition in inferior colliculus neurons.

Most criteria for establishing GABA as an inhibitory neurotransmitter in the central nucleus of inferior colliculus (ICc) have been satisfied, but the role of GABA in acoustic coding in ICc is not established. The present study examined this issue by evaluating the effects of iontophoretic application of agents that alter activity at GABA receptors on potential forms of acoustically-evoked inhibition in ICc neurons. Application of the GABAA antagonist, bicuculline, selectively blocked the firing reduction at high intensities observed during non-monotonic rate-intensity functions in ICc neurons. Binaural inhibition was selectively blocked by bicuculline and increased by nipecotic acid. Application of GABA, nipecotic acid (GABA uptake inhibitor) and a benzodiazepine (flurazepam), which enhances the action of GABA, increased the duration and intensity of ipsilateral inhibition and response pause, while bicuculline blocked these acoustically-evoked inhibitory events. Offset inhibition was increased by nipecotic acid application and reduced by bicuculline with the appearance of an offset peak. The present data support an important role for GABA as a neurotransmitter, mediating, in part, non-monotonicity, binaural inhibition, response pause and offset inhibition in ICc neurons. Alterations of these GABA-mediated inhibitory phenomena may occur in auditory dysfunctions observed with aging and audiogenic seizures.

Acoustic Stimulation↗
PubMed1990

Audiogenic seizure severity and hearing deficits in the genetically epilepsy-prone rat.

Hearing deficits have been observed in rodents that are susceptible to audiogenic seizures (AGS), including the genetically epilepsy-prone rat (GEPR). AGS susceptibility can be induced in normal animals by treatments that damage the cochlea. In this study, we measured the relative degree of hearing loss in animals from the GEPR substrains that exhibit different degrees of AGS severity and examined the relationship between the deficit and the AGS severity. Auditory brain stem response (ABR) thresholds to clicks in the GEPR substrain that exhibits exclusively maximal AGS severity (GEPR-9) were significantly elevated, and latencies for ABR peaks I, III, and IV were significantly increased as compared to normal Sprague-Dawley rats. ABR thresholds for the substrain of GEPRs were even higher than those in the GEPR-9, and ABR waveforms were distorted. ABR peak IV was significantly longer than normal in the GEPR-3 substrain, as were mean interpeak intervals and central conduction times. These data indicate that significant hearing deficits occur in the GEPR-3 substrain. In non-AGS-susceptible progeny of the GEPR-9 [GEPR-0(9)], ABR thresholds were not significantly different from normal. These data along with studies of ABR thresholds in thyroid-deficient rats suggest that an inverted U-shaped relationship exists between hearing deficit and AGS severity. That is, moderate threshold elevations are associated with increasing AGS severity, but when the hearing deficit exceeds a certain level, a decrement in AGS severity occurs.

Acoustic Stimulation↗
PubMed1989

Non-N-methyl-D-aspartate receptors may mediate ipsilateral excitation at lateral superior olivary synapses.

Principal cells of the lateral superior olivary nucleus (LSO) are thought to receive a direct excitatory input from spherical bushy cells located in the ipsilateral ventral cochlear nucleus (VCN) and an indirect input from the contralateral VCN globular bushy cells via a secure synapse in the medial nucleus of the trapezoid body (MNTB). MNTB bushy cells project to the somata and proximal dendrites of LSO principal cells. LSO neurons display phasic 'chopper' temporal response patterns to ipsilateral tone-burst stimuli at characteristic frequency (CF), while binaural stimuli suppress this ipsilaterally evoked activity. This suppression is sensitive to interaural differences in intensity, phase and time, suggesting a role for these neurons in the localization of sound in space. In the present study, the nature of the neurotransmitter mediating fast ipsilateral excitation of LSO neurons was examined using iontophoretic application of excitant amino acid (EAA) agonists and antagonists. N-methyl-D-aspartate (NMDA) and quisqualate (QUIS) were used as agonists, while the selective NMDA receptor antagonist D. L-2-amino-5-phosphonovaleric acid (APV), and the non-selective receptor EAA antagonist cis-2,3-piperidine-dicarboxylic acid (PDA) were used to study ipsilaterally evoked neuronal responses. In 3 additional experiments the selective non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) replaced PDA. Ipsilateral, tone-evoked and spontaneous activities were generally enhanced by EAA agonists while partial blockade of tone-evoked, ipsilateral excitation was observed with EAA antagonists. Both PDA and DNQX more effectively blocked ipsilateral tone-evoked excitations and spontaneous activity than did the NMDA-receptor antagonist, APV.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed1989

On the role of GABA as an inhibitory neurotransmitter in inferior colliculus neurons: iontophoretic studies.

Significant neurochemical, immunocytochemical, and ligand binding studies support a role for GABA as an inhibitory neurotransmitter in the inferior colliculus (IC). The present study attempted to satisfy some of the remaining criteria for establishing transmitter identity by utilizing iontophoretic application onto IC neurons of agents affecting the action of gamma-aminobutyric acid (GABA). The agents examined include GABA, a GABAB agonist (baclofen), a GABAA antagonist (bicuculline), a GABA uptake inhibitor (nipecotic acid), and a benzodiazepine (flurazepam), thought to exert its actions on the GABA receptor complex. Application of GABA results in inhibition of the spontaneous firing and acoustically evoked responses of inferior colliculus neurons. The inhibitory effect of GABA is enhanced by the simultaneous application of nipecotic acid or flurazepam. These agents as well as baclofen produce firing reductions when applied alone in higher doses. The effect of GABA can be blocked by application of bicuculline, and acoustically evoked (binaural) inhibition can also be selectively blocked by low doses of this GABAA antagonist. These data along with previous studies utilizing different techniques fulfill many of the criteria for establishment of GABA as an important inhibitory transmitter in the inferior colliculus.

Acoustic Stimulation↗
PubMed1989

Effects of excitant amino acids on acoustic responses of inferior colliculus neurons.

Iontophoretic application of the excitant amino acids (EAAs), glutamate, aspartate and N-methyl-D-aspartate (NMDA) resulted in increased acoustically evoked and spontaneous firing of most neurons in the central nucleus of inferior colliculus (ICC). The excitatory effects of these EAAs were blocked by simultaneous application of EAA antagonists which selectively block the NMDA receptor subtype, 2-amino-5-phosphonovalerate or D-alpha-aminoadipate and to a lesser extent with non-selective EAA antagonists, such as glutamic acid diethylester. Application of NMDA receptor-selective EAA antagonists alone greatly reduced the firing of most ICC neurons examined, but non-selective EAA antagonists either increased or produced little change in firing of most ICC neurons examined. In this and previous studies cholinergic agonists were found to increase the firing of ICC neurons, but the cholinergic agonists were less effective in exciting ICC neurons than EAA agonists. Cholinergic antagonists in a previous study were considerably less effective in inhibiting the discharge of ICC neurons than were the EAA antagonists in the present study. These results, in conjunction with previous neurochemical and anatomical localization studies, support a possible role of an EAA as a candidate for afferent excitatory transmitter in neurons of the inferior colliculus.

2-Amino-5-phosphonovalerate↗
PubMed1988

Excitant amino acids and audiogenic seizures in the genetically epilepsy-prone rat. I. Afferent seizure initiation pathway.

The afferent pathway involved in initiation of audiogenic seizures in the genetically epilepsy-prone rat was investigated by bilateral microinfusion of the excitant amino acid antagonist 2-amino-7-phosphonoheptanoate into the major brain stem and subcortical nuclei of the auditory system. This antagonist has been shown to possess anticonvulsant properties in other seizure models, and an excitant amino acid has been implicated as a putative neurotransmitter in several of these nuclei. Seizure severity was significantly reduced following infusion of this agent into the cochlear nucleus, superior olivary complex, inferior colliculus, and medial geniculate body. Many of these animals exhibited a complete blockade of seizures. The smallest effective dose in the cochlear nucleus and the medial geniculate body was 5 nmol per side. The smallest effective dose in the olive was 1 nmol, and in the inferior colliculus 0.1 nmol per side was protective. The onset of anticonvulsant effectiveness was earliest in the inferior colliculus. These findings showed that the inferior colliculus was the most sensitive auditory center to the anticonvulsant action of 2-amino-7-phosphonoheptanoate and that imbalance between inhibitory and excitatory transmission within this brain structure may be crucial in the initiation of audiogenic seizures in the genetically epilepsy-prone rat.

2-Amino-5-phosphonovalerate↗
PubMed1988

Excitant amino acids and audiogenic seizures in the genetically epilepsy-prone rat. II. Efferent seizure propagating pathway.

Previous studies indicate that the inferior colliculus is the brain stem auditory nucleus most sensitive to the chemical blockade of audiogenic seizures in the genetically epilepsy-prone rat. Other auditory structures do not appear to be as important. This study attempted to define the efferent pathways involved in propagation of the seizure from the colliculus to the spinal cord where the motor components of the convulsion are generated. This study also determined whether certain nuclei which have been implicated in the propagation of seizures in other epilepsy models are involved in audiogenic seizures. The excitant amino acid antagonist, 2-amino-7-phosphonoheptanoate, was infused bilaterally into several of those sites. The drug was effective in significantly reducing seizure severity with infusion of 5 nmol bilaterally into the midbrain and the pontine reticular formation or the substantia nigra. However, similar drug doses were not effective when infused into the entopeduncular nucleus even though prominent behavioral effects were observed with this infusion. Infusion of 2-amino-7-phosphonoheptanoate into the prepiriform cortex resulted in a small but significant reduction in seizure severity. These results suggest that inhibition of excitatory transmission within the substantia nigra and the reticular formation effectively blocks the output pathway for the audiogenic seizures, whereas the role of the prepiriform cortex in this process is relatively minor.

2-Amino-5-phosphonovalerate↗
PubMed1988

The genetically epilepsy-prone rat.

1. The genetically epilepsy-prone rat (GEPR) is a valuable model for investigating mechanisms involved in epilepsy because of the controllable nature of the convulsions and their genetic origin. 2. The GEPR exhibits audiogenic seizures (AGS) and also displays higher than normal sensitivity to convulsant drugs, kindling, electroshock and hyperthermic seizures. 3. An abnormal electroencephalographic pattern and increased thresholds for auditory evoked potentials from the cochlea and brainstem are observed in the GEPR. 4. Afterdischarge-like responses and decreased sound-induced inhibition are observed in neurophysiological recordings from neurons of the inferior colliculus (IC) in the GEPR. 5. Significant deficits of norepinephrine and serotonin are observed in many regions of the GEPR brain. 6. Increases in the number of GABAergic neurons and a reduced effectiveness of iontophoretically-applied GABA are observed in the IC of this animal. 7. GABA agonists or an excitant amino acid (EAA) antagonist block AGS susceptibility when microinjected into brainstem auditory nuclei of the GEPR up to the level of IC. 8. A GABA antagonist or an EAA agonist induces susceptibility to AGS in normal rats following microinjection into IC. An increase in EAA release in IC during AGS in the GEPR is also observed. 9. This increased release of EAA and the reduced effectiveness of GABA in IC may be important seizure initiation mechanisms in the GEPR. 10. The AGS pathway in the GEPR appears to involve the auditory nuclei up to the IC as well as the brainstem reticular formation and substantia nigra but not the entopenduncular nucleus or hippocampus.

Animals↗
PubMed1987

Strychnine alters the fusiform cell output from the dorsal cochlear nucleus.

Anatomical and physiological evidence suggests that fusiform cells, the major output neurons of the dorsal cochlear nucleus (DCN), receive significant inhibitory input. Fusiform cells often display strongly non-monotonic rate-intensity functions and pauser-buildup or buildup tone-evoked temporal responses, patterns which may be mediated by inhibitory neurotransmitters. Other neurons located within the fusiform cell layer or in the more superficial molecular layer display varied rate-intensity functions and temporal responses. Neurons displaying response properties characteristic of fusiform cells are sensitive to iontophoretic application of the inhibitory amino acid neurotransmitter, glycine. Application of the glycine receptor antagonist, strychnine, alters the non-monotonic portion of the rate-intensity function at doses which do not alter spontaneous activity or near-threshold tone-evoked responses. These neurons are also sensitive to GABA and the GABAB agonist, (-)-baclofen, but are insensitive to the GABAA antagonist, bicuculline. DCN neurons which display monotonic rate-intensity functions and temporal response properties different than those associated with fusiform cells are sensitive to bicuculline, (-)-baclofen, and GABA. These data suggest that a glycinergic input onto fusiform cells may control the non-monotonic nature of the response of these neurons near characteristic frequency and therefore may contribute significantly to the nature of the output of the DCN.

Acoustic Stimulation↗
PubMed1987

Mechanisms of anticonvulsant drug action. I. Drugs primarily used for generalized tonic-clonic and partial epilepsies.

The mechanisms by which the clinically effective anticonvulsant drugs act include effects on neurotransmitter action, effects on repetitive neuronal firing mechanisms, effects on neuronal networks, and effects on neuronal ionic transport. The combination of effects possessed by each individual agent along with its pharmacokinetic properties determine the usefulness of each agent. Phenytoin, carbamazepine and phenobarbital are effective in generalized tonic-clonic and partial epilepsies. Phenytoin exerts important effects on neuronal sodium and calcium ion transport, reduces repetitive firing, reduces excitation in neuronal networks of the brainstem reticular formation, and produces some decrease in the effect of the inhibitory transmitter, gamma-aminobutyric acid (GABA). Carbamazepine blocks repetitive firing mechanisms, reduces excitation in neuronal networks with some effect on sodium and potassium ion transport, and has effects on the actions of norepinephrine, adenosine and perhaps acetylcholine. Phenobarbital enhances the action of GABA with some reduction of repetitive firing and reduces excitation in reticular formation neuronal networks.

Anticonvulsants↗
PubMed1987

Mechanisms of anticonvulsant drug action. II. Drugs primarily used for absence epilepsy.

The usefulness of the anticonvulsant drugs is determined by the mechanisms by which the agent acts and its pharmacokinetics. The general mechanisms of action of these agents include (1) effects on neurotransmitter action, (2) effects on repetitive neuronal firing mechanisms, (3) effects on neuronal networks, and (4) effects on neuronal ionic transport. Ethosuximide, valproic acid and clonazepam are used primarily in absence epilepsy. Valproic acid is also effective against generalized tonic-clonic epilepsy. Diazepam is used primarily in status epilepticus. Valproic acid enhances gamma aminobutyric acid (GABA)-mediated inhibition, reduces repetitive firing, and reduces both inhibition and excitation in neuronal networks. Clonazepam and diazepam enhance the inhibitory action of GABA, decrease inhibition in neuronal networks and affect calcium ion transport with lesser effects on repetitive firing. Ethosuximide reduces inhibition in neuronal networks, may interact with dopamine, and possibly affects sodium and potassium ion transport. Further work is needed to assess the degree of involvement of these effects in the anticonvulsant action versus the adverse effects of these agents.

Anticonvulsants↗
PubMed1986

Inferior colliculus neuronal response abnormalities in genetically epilepsy-prone rats: evidence for a deficit of inhibition.

The genetically epilepsy-prone rat (GEPR) is abnormally susceptible to induction of seizures by acoustic stimulation. The inferior colliculus (IC) is critically important to audiogenic seizure susceptibility. The GEPR is more susceptible to induction of audiogenic seizures at 12 kHz than at other pure tone frequencies. IC neurons in the GEPR exhibit significantly elevated response thresholds and broader tuning characteristics than normal. These findings along with previous neurophysiological and anatomical data suggest that a hearing deficit occurs in the GEPR. IC neurons in the GEPR exhibit a significantly elevated incidence of a response pattern with a peak of activity at the beginning and end of the stimulus, the onset-offset response. This response pattern occurs at 12 kHz and at characteristic frequency with high stimulus intensities and may represent an afterdischarge phenomenon. The onset-offset pattern may be a manifestation of central mechanisms developed to compensate for reduced peripheral auditory input that appears to be involved in the hearing deficit of the GEPR. Such compensatory mechanisms may involve alterations of the actions of neurotransmitters of the brain-stem auditory nuclei. GABA is implicated as an inhibitory transmitter in the IC. Iontophoretic application of GABA or a benzodiazepine produces significantly less inhibition of IC neurons of the GEPR than of the normal rat. Endogenous sound-induced (binaural) inhibition which is suggested to be GABA-mediated is also significantly reduced in IC neurons of the GEPR. Iontophoresis of the GABAA antagonist, bicuculline, often converts normal response patterns in the IC to onset-offset responses seen with high incidence in GEPR IC neurons, suggesting that the decreased effectiveness of GABA may lead to the onset-offset prevalence. This reduced effectiveness of inhibition may be unable to compensate for the rise in the putative excitatory transmitter, aspartate, in IC during high intensity acoustic stimulation in the GEPR. These altered transmitter actions may be important mechanisms subserving initiation of audiogenic seizures in the genetically epilepsy-prone rat.

Acoustic Stimulation↗
PubMed1986

Neuronal response abnormalities in the inferior colliculus of the genetically epilepsy-prone rat.

The genetically epilepsy-prone (GEP) rat is susceptible to seizure induction by acoustic stimuli. The inferior colliculus (IC) has been implicated as being critically important in audiogenic seizure susceptibility based on lesion, electrical stimulation, and focal implantation experiments. The current study determined that GEP rats were most susceptible to seizure induction by pure tone bursts at 100 dB at a frequency of 12 kHz. IC neurons in the GEP rat exhibited a significantly elevated incidence of a particular response pattern at 12 kHz and at characteristic frequency. This pattern consisted of a peak at the beginning and end of the stimulus (onset-offset response). This response pattern only occurred with high intensity stimuli approximating those which induce seizures and may represent an afterdischarge phenomenon. The response threshold was significantly elevated and tuning characteristics were also significantly altered in IC neurons of GEP rats as compared to normal IC neurons. The latter two findings may be related to the deficit of hearing which is reported in the GEP rat. The increased incidence of onset-offset responses may be due to a decreased efficacy of inhibition in the GEP rat neurons as compared to normal rat neurons.

Acoustic Stimulation↗
PubMed1986

Induction of audiogenic seizure susceptibility by focal infusion of excitant amino acid or bicuculline into the inferior colliculus of normal rats.

N-Methyl-D-aspartate (NMDA) (10 to 20 nmol) or bicuculline (15 to 50 pmol) in 0.5 microliter was infused bilaterally into the inferior colliculus or the deep layers of superior colliculus (DLSC) in normal rats, and the response to high intensity acoustic stimulation was examined. Thirty-five percent of rats receiving NMDA infusions and 42% of animals receiving bicuculline infusions into the inferior colliculus exhibited sound-induced seizures exclusively that were behaviorally similar to audiogenic seizures displayed by genetically epilepsy-prone rats. Rats receiving microinjections into the DLSC did not display sound-specific seizures. A combined pattern of spontaneous and sound-induced seizures was seen in some rats with both drugs and loci of microinjection. These data and previous studies support a role for increased excitant amino acid action and decreased efficacy of GABA in the inferior colliculus as important mechanisms involved in genetic susceptibility to audiogenic seizures.

Acoustic Stimulation↗
PubMed1986

Decreased effectiveness of GABA-mediated inhibition in the inferior colliculus of the genetically epilepsy-prone rat.

The inferior colliculus (IC) is a critical site for induction of audiogenic seizures in the genetically epilepsy-prone rat (GEPR). Abnormal response properties observed in inferior colliculus neurons of that strain include a high incidence of onset-offset responses which may be a form of afterdischarge. These response abnormalities may involve altered actions of neurotransmitters in that region of the brain. GABA is implicated as a transmitter in endogenous sound-induced inhibition in the inferior colliculus. Endogenous inhibition and the actions of agents that affect GABA receptors were examined in inferior colliculus neurons in epileptic and normal rats. The iontophoretic dose (current) of GABA required to suppress neuronal firing in the epilepsy-prone rat was significantly greater than that required in neurons of the normal rat. A form of endogenous (binaural) inhibition in inferior colliculus neurons, which is proposed to be GABA-mediated, was also significantly reduced in the epilepsy-prone rat as compared with the normal rat. A benzodiazepine (flurazepam) which enhances the action of GABA in many brain sites including the inferior colliculus was significantly less effective than normal when applied iontophoretically onto the same neurons of the epilepsy-prone rat. The GABAA antagonist, bicuculline, which blocks the effect of GABA on inferior colliculus neurons, frequently induced the onset-offset response in neurons not previously exhibiting this pattern. These findings suggest that the reduction of GABA-mediated inhibition in the genetically epilepsy-prone rat may result in the increased incidence of afterdischarges in neurons of the inferior colliculus and may serve as an important mechanism of epileptogenesis in audiogenic seizures in this genetic form of epilepsy.

Animals↗
PubMed1985

Comparative effects of convulsant drugs on the sensory responses of neurons in the amygdala and brainstem reticular formation.

The sensory responses of neurons in the amygdala and mesencephalic reticular formation in the cat were enhanced following the intravenous administration of subconvulsant doses of bicuculline, strychnine, bemegride, pentylenetetrazol and physostigmine. The degree and intensity of the enhancement of the response was considerably greater in the reticular formation than in the amygdala. The latency of the response in simultaneously-recorded pairs of neurons in the amygdala and reticular formation was significantly shorter in the mesencephalic reticular formation. The enhancement induced by convulsants does not appear to be transmitter-specific, since enhancement was produced with sequential administration of convulsant drugs which affect gamma-aminobutyric acid (GABA), glycine or acetylcholine. These findings suggest that the reticular formation is involved, to a larger degree than the amygdala, in the ability of sensory stimuli to initiate generalized convulsive seizures in animals treated with these convulsant drugs. The enhancement of the response in the hippocampus and cortex, which has previously been shown to exhibit a longer latency and a lower degree of enhancement than the reticular formation, coupled with the findings in the amygdala, suggest that the reticular formation may mediate the enhancement of the response of these other regions of the brain. The spread of the enhancement of the response to other structures in the brain via the widely distributed output pathways from the reticular formation may lead to initiation of generalized seizures by a recruitment-like process, which may involve enlargement of the sensory hyperresponsive neural network of the brain until a critical neural mass is reached and initiation of seizures results.

Amygdala↗
PubMed1985

Mechanisms of sensory seizures: brain-stem neuronal response changes and convulsant drugs.

Generalized convulsive seizures can be triggered by sensory stimuli in animals treated with subthreshold levels of convulsant drugs. The sensory responses of the brain-stem reticular formation (RF) are extensively enhanced before seizure initiation with bicuculline, strychnine, pentylenetetrazol, physostigmine, and several other convulsants. The responses of RF neurons are more greatly enhanced than other nonprimary neurons in the hippocampus, amygdala, and cortex. The action of systemically administered convulsants involves direct effects on reticular neurons, because RF response enhancement is also seen with iontophoresis. RF neuronal response enhancement does not appear to involve actions of convulsants on specific neurotransmitters, because agents that act on different transmitters enhance the responses of the same RF neuron when given sequentially. Anticonvulsant drugs reverse the effects of convulsants on reticular neurons. The convulsant-induced response enhancement in the RF may involve blockade of inhibitory postsynaptic potentials and/or threshold reduction, effects observed in vitro. RF neurons may be most susceptible to convulsant action because these agents block habituation and other mechanisms that normally restrict RF neuronal responsiveness. The massive synchronization of reticular neuronal firing by sensory stimuli may induce seizures by intense output over widespread RF projection pathways analogous to the afterdischarge seizures seen with electrical stimulation of the RF.

Animals↗